San Francisco, CA (UroToday.com) During the general session on optimizing diagnosis and treatment of clinically significant nonmetastatic prostate cancer session at the Annual ASCO GU 2019 meeting in San Francisco, CA, Drs. Sridhar, Briganti, and Payne presented on the treatment of high-risk localized prostate cancer, and issues related to intensification and deintensification of treatment from medical oncology, urology, and radiation oncology perspective.

Dr. Sridhar started her talk with a case summary of a high risk localized prostate cancer and requested an audience response on the treatment options. She then summarized the incidence and definition of high risk localized prostate cancer, which accounts for 15% of men presenting with local disease and predisposes the patient to a high risk of recurrence and cancer-related death. Since biochemical recurrence is not a good surrogate for survival and there is significant heterogeneity in clinical behavior and outcomes, there is a need for novel molecular biomarkers or imaging approaches to improve risk stratification. This may also change the definition of high-risk disease in future which will better tailor a therapeutic approach and determine clinical trial eligibility.

She summarized the results of NCIC PR3 study which showed that ADT+RT is better than ADT alone. She also talked about the recently published SPCG4 study which showed that radical prostatectomy is beneficial in patients with long life expectancy. Therefore, there is a real need for a validated surrogate endpoint of survival and ICECAP initiative has reported that metastasis-free survival is a strong surrogate endpoint for overall survival in localized prostate cancer.

Despite local treatment of high-risk prostate cancer, biochemical failure, and cancer-specific mortality is high. Systemic therapies have shown a clear survival advantage in advanced cancer, and there may be a role for starting systemic treatment in early prostate cancer, as shown recently by STAMPEDE and CHAARTED trials. She summarized several studies which have shown that intensification of RT by adding ADT to RT significantly improves survival, and therefore ADT+RT is recommended by all guidelines. However, ADT is not without side effects. To minimize the side effects associated with ADT, studies have looked at a shorter duration of treatment, however the study comparing 18 vs 36 months of ADT was underpowered to show equivalence, and so should be viewed cautiously . Shorter duration of ADT has therefore not been widely adopted. There are also studies underway looking at intensification of RT with systemic chemotherapy, but longer follow-up is needed.

Similarly, adding ADT to radical prostatectomy has shown improvement with local control, but no improvement in DFS or OS. She also talked about the Prioriti and AFU-GETUG 20 studies that will offer a contemporary look at adding ADT to radical prostatectomy. Adding androgen receptor pathway inhibitors such as Abiraterone, Enzalutamide, have not shown improved outcomes in terms of complete pathologic response and there is an opportunity to test novel combinations. According to Dr. Sridhar, genomic profiling of patients such as the GUNS study may be the way of the future. Other studies such as PUNCH and ACDC studies are ongoing evaluating systemic chemotherapy in the neoadjuvant setting along with radical prostatectomy.

In summary, Dr. Sridhar mentioned that this is an exciting time in the field of high risk localized prostate cancer with many trials across many settings incorporating systemic treatment into their current treatment paradigm. The goal is to individualize and personalize therapy based on both biomarkers and a better understanding of the disease at the molecular level.

Dr. Briganti followed Dr. Sridhar’s excellent summary with intensification/deintensification options with surgery. He mentioned that SPCG 15 is an ongoing RCT looking at comparing primary radical prostatectomy and primary RT +ADT for locally advanced prostate cancer. Dr. Briganti highlighted the strength of surgery which is tailoring the surgical approach based on patient’s risk with potential decreased risk of over-treatment. He also pointed out that patients with multiple high-risk factors will benefit most from intensification. Before surgery, there is no role of ADT currently, but results of some trial as previously stated are awaited. During the surgery, extended lymph node dissection or wider surgical dissection may improve cancer control, based on results of MRI or frozen section. After the surgery, the use of RT and ADT can prevent local recurrence. Surgical approach can also be tailored to improve functional outcomes in patients to perform a nerve-sparing radical prostatectomy based on MRI results.

Dr. Briganti also mentioned that in some high-risk patients, performing extended and super extended lymph node dissection improves staging, but there is no randomized data available looking at cancer-specific outcomes. After surgery, due to the availability of a final pathology report, adjuvant RT can be tailored to avoid overtreatment. Postponing RT until early PSA progression or in patients with less pathologic risk factors also helps with deintensification. Some of the trial results are awaited in this arena. He also talked about patients with positive node disease and that the EAU guidelines support expectant management in carefully selected patients which is possible because of extended lymph node dissection.

Dr. Briganti summarized his outstanding talk by stressing that surgery allows for truly individualized approaches decreasing overtreatment in the management of high-risk disease in approximately a third of the high-risk patients, but multimodal treatment may be necessary for some patients.

Professor Payne, a radiation oncologist, then started her talk by presenting the challenges faced by a high-risk prostate cancer patient such as local control and prevention of future distant micrometastatic diseases, which may be present at the time of initial diagnosis. These patients need multimodal treatment while balancing side effects.

Evolution of IMRT, brachytherapy, VMAT has allowed more focused treatment while avoiding side effects and several randomized studies have shown dose escalation results in improved biochemical free survival and delayed future systemic treatment. She pointed out the fascinating data presented from PACE-B trial this morning, showing no difference in acute G2+ toxicities in patients receiving SBRT. Dose escalation showed improved survival for intermediate and high-risk prostate cancer patients only in a large non-randomized retrospective study from NCDB. This suggests intensification for high-risk patients and deintensification for low-risk patients receiving RT.

Professor Payne then summarized the ASCENDE-RT study, which showed that men treated with LDR-brachytherapy boost were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years compared to the EBRT boost group; however, there was increased GU toxicity after LDR-brachytherapy boost. HDR brachytherapy in combination with EBRT is a well-established treatment option for intermediate and high-risk prostate cancer with randomized data showing a 31% risk reduction in biochemical and clinical relapse. Besides, there was no evidence that quality of life deteriorated with increased follow-up time. Long term follow-up data shows 83% cancer-specific survival at ten years and 75% survival at 15 years following EBRT and HDR brachytherapy. She also presented the recent data from the FLAME study which compared toxicity rates in patients with localized prostate cancer treated with standard fractionated EBRT with or without an additional integrated boost to the macroscopically visible tumor. In intermediate- and high-risk prostate cancer patients, focal dose escalation integrated with standard EBRT did not increase GU and GI toxicity when compared to the standard treatment up to two years after treatment. This suggests that the described focal dose escalation technique is safe and feasible. The CHHiP study showed that hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localized prostate cancer. Long term follow-up is awaited on these studies. There is no level 1 evidence comparing RT to radical prostatectomy in high-risk patients, but some retrospective studies favor RT.

She concluded her talk by mentioning that evolution of RT intensification has demonstrated benefits in treatment outcomes without increased toxicity. Future intensification should be aimed at men with higher risk disease determined by enhanced risk stratification with deintensification for lower risk patients. All treatment options must be discussed with the patient and patient’s comorbidities, choices and preferences must always be considered.

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